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Module 3 > Cancer Immunology and Immune suppression > Flashcards

Cancer Immunology and Immune suppression Flashcards

1
Q

What is the evidence of an immune response to cancer?

A

immune suppression increases tumour incidence; inflammatory immune responses can also promote tumour incidence; presence of immune response associated with prognosis

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2
Q

Give examples of inflammatory immune responses promoting tumour incidence?

A

H.pylori and stomach cancer; hep B and liver cancer; pancreatitis and pancreatic cancer

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3
Q

What cytokines promote tumour clearance?

A

IFNy and IL-2

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4
Q

How does advanced cancer perpetuate immune dysfunction?

A

cell heterogeneity; TCR dysfunction; desnity of antigen on the tumour cells may be lower than the threshold for recognition; host system may be too overwhlemed; defective APCs; MDSC

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5
Q

How does cancer cause TCR dysfunction?

A

change in quality (phosphorylation); change in quantitty (proteolysis) due to tumour microenvironment

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6
Q

Which cells is TCR dysfunction in cancer first seen in?

A

TILs then in PBMCs

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7
Q

How does cancer overwhelm the immune system?

A

continuous shedding of tumour associated antigen may induce tolerance; local Th2 response is stimulated; T cells less IL2 responsive

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8
Q

How do cancers cause defective APCs?

A

lack of MHC-I expression of B7; lack of costimulation- anergy ; VEGF immunsuppresses APCs

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9
Q

What do monocytic MDSCs differentiate to in tumour sites?

A

tumour associated macrophages and inflammatory DCs

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10
Q

What are the 2 types of MDSC?

A

monocytic type and polymorphonuclear type

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11
Q

What attracts monocytic MDSCs to the tumour site?

A

chemokines CCL2 and CCL5 and grwoth factor CSF-1

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12
Q

What controls the differentiation of TAMs?

A

HIF-1a increase and STAT3 decrease

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13
Q

What can TAMs differentiate into

A

M1 and M2 types

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14
Q

What is the effect of both M1 and M2-like TAMs?

A

suppression of T cells

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15
Q

How do M1-like TAMs inhibit T cell function?

A

NO

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16
Q

How do M2-like TAMs inhibit T cell function?

A

arginase 1

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17
Q

What does the functional outcome of the MDSC depend on/

A

tumour microenviroment

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18
Q

When are MDSCs formed?

A

in the context of cancer, normally become monocytes or PBMCs

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19
Q

What factor in the cancer microenvironment helps stimulate formation of TAMs?

A

hypoxia and VEGF

20
Q

What are the features of tumour mediated immune evasion?

A

loss of expression of mutation of tumour antigens; loss of antigen processing and presentation-MHC-1; expression of immunosuppressive factors; activation of Tregs; expression of decoys- soluble circulating tumour antigens; clonal exhaustion; tolerane induced by continuous shedding of TAAs; expression of PD-L1; loss of Fas;; intrisinsic resistance to apoptosis

21
Q

What are the authors of the hallmarks of cancer?

A

Hanahan and Weinberg

22
Q

What are hte hallmarks of cancer?

A

sustained proliferative signalling; resisting cell death; evading growth suppressors; activating invasion and metastasis; enabling replicative immortality; inducing angiogenesis; avoiding immune destruction

23
Q

What is the effect of APCs producing IDO and arginase?

A

inhibits CD3 function on CTLs

24
Q

What is the effect of IL-10 and TGFb produced by APCs?

A

induces Tregs which inhibit CTLs

25
Q

What are hte major mechanisms by which CTLs kill target cells?

A

perforin/granzyme and Fas/FasL

26
Q

How does the tumour have intrinsic resistance to apoptosis?

A

upregulation of anti-apoptotic proteins Bcl2, survivin

27
Q

What factors barrier the activation; proliferation and survival of naive tumour specific T cells?

A

CTLA-4; Tregs; TGFb; IL-10; lack of TLR signals ; lack of yc cytokines

28
Q

What prevents the activated tumour specific T cell migrating to the tumour site?

A

lack of chemokine expression by tyumours; lack of chemokine receptors on T cells

29
Q

What inhibits the effector functions of tumour-specific T cells?

A

Tregs; PD-L1; TGFb; IL-10; IDO; arginase; iNOD; VEGF

30
Q

What suggests taht ovarian tumours may be amenable to immune attack?

A

high numbers of TILs associated with better prognosis; express tumour antigens e.g CA-125

31
Q

How do ovarian cacners suppress the immune repsonse?

A

high Tregs associated with increased resistance to chemo and decreased survival; icnreased expression of PDl1; lipids in ascites can suppress NK activation; TNFa production generates an autocrine tumour-promoting network

32
Q

What is found on the intracellular domain of PD-1?

A

ITSM and ITIMs

33
Q

What binds to ITSM on intracellular domain of PD-1?

A

SHP-2

34
Q

What happens when PD-1 is activated?

A

SHP2 is able to dephosphorylate proximal signalling kinases of the TCR

35
Q

Which cells express PD-1?

A

activated T and B cells; macropahges

36
Q

What scientists were invovled in checkpoint inhibition mAbs?

A

Allison- CTLA4 and Honjo- PD-1

37
Q

What does engagement of PD-1 result in?

A

T cell anergy

38
Q

What was the recent clinical success of anti-PD1?

A

complete of partial response to different types of cancer- melanoma; renal cell carcinoma

39
Q

What is the name for the anti-PD1?

A

nivolumab

40
Q

What represents a challenge in the anti-PD1 therapy?

A

there is no correlation between tumour PD-L1 expression and response to therapy- unknown why some patients respond and others don’t

41
Q

What is the name for the anti-CTLA4?

A

ipilumumab

42
Q

What is nivolumab approved for?

A

melanoma and small cell lung cancer

43
Q

What is ipilimumab approved for?

A

advanced melanoma

44
Q

What is the efficacy of ipilumamab?

A

aroudn 4 months increase in overall survival

45
Q

What is the difference between anti-CTLA4 and anti-PD1/PDL1?

A

anti-CTLA4 has higher increase in overall suvival but there are higher toxicities

Module 3 (33 decks)

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